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Panel discussion recurrent cervical cancer

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Panel discussion recurrent cervical cancer

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While the role of radiation therapy in carcinoma cervix management is undauntable for all stages. Recurrent carcinoma cervix need a lot of personalisation

While the role of radiation therapy in carcinoma cervix management is undauntable for all stages. Recurrent carcinoma cervix need a lot of personalisation

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Panel discussion recurrent cervical cancer

  1. 1. Dr Ajeet Kumar Gandhi MD (AIIMS); DNB; UICCF (MSKCC, USA) Assistant professor, Radiation oncology Dr RMLIMS, Lucknow
  2. 2. CERVICAL CANCER: SCENARIO **Source: Globocan, 2012  5,28,000 cases diagnosed annually worldwide with 2,66,000 deaths  >85% of the global burden of cancers occur in developing countries  2nd most common cancer in India with 1,23,000 diagnosis and 67,000 deaths every year
  3. 3. Recurrent cervical cancer  Pelvic relapse rates* in definitively treated patients: 20-40%  Approximately 2/3rd are pelvic failures  Approximately 80% are in the irradiated field and 20% outside this  Treatment is very challenging, limited options  Limited literature and ultimate outcome is poor. *Andreu Martinez FJ et al. Clin Transl Oncol 2005;7:323-331
  4. 4. Residual or recurrent?? How do you in your clinical practice define a patient treated definitively with concurrent chemoradiation followed by brachytherapy to have: 1. Persistent disease/Recurrent disease? 2. Time point after completion of treatment for labelling persistent disease?? 3. Biopsy persistent disease??
  5. 5.  There are no definite criteria for labelling a patient to be having persistent or recurrent disease  Persistent/residual disease: Disease evident within 6 months of the primary treatment.  Recurrent disease: Development of nodal or distant metastasis 6 months after the documentation of a complete regression of disease *Heron CW. Clin Radiol 1988; 39:496–501
  6. 6. 45 Year, Carcinoma cervix stage IIB treated definitively with EBRT 50.4 Gray in 28 fractions over 5.5 weeks with concurrent Cisplatin weekly and HDR-ICRT 7 Gray in 3 fractions, now have a persistent disease at cervix, approximately 2*2 cm (biopsy proven to be SCC) after 4 months of the completion of therapy. Metastatic work up negative. PS (ECOG 1). Tolerated earlier treatment well. 1. Salvage surgery 2. Re-irradiation/Consolidative RT 3. Chemotherapy followed by Surgery 4. Chemotherapy 5. Observation alone
  7. 7.  1994-2001; Stage 1b1-IVA treated with CTRT  Cervical biopsy taken 8-10 weeks after completion of treatment  Of 111 biopsy specimens, 21 positive for viable cells (19%)  Salvage surgery performed in 13/21 patients  Patients not undergoing salvage surgery (all died of progressive disease)
  8. 8.  1994-2011; Stage 1b1-IVA treated with CTRT  Cervical biopsy taken 8-10 weeks after completion of treatment  Of 345 biopsy specimens, 84 positive for viable cells (24.3%)  Salvage surgery performed in 61/84 patients  Residual disease after (chemo)radiation was an independent poor prognostic factor (hazard ratio, 3.59; 95% confidence interval, 2.18Y5.93; P G 0.001).  More radical surgery was not associated with improved DFS (P = 0.81) but did result in significantly more severe morbidity
  9. 9. Persistent/Residual disease following definitive CTRT 1. Salvage surgery 2. Chemotherapy followed by Surgery 3. Re-irradiation/Consolidative RT 4. Chemotherapy 5. Observation alone
  10. 10. Recurrent cervical cancer: Investigations  Pelvic examination (if required under Anaesthesia)  Biopsy of the recurrent local or pelvic disease??
  11. 11. Recurrent cervical cancer: Radiological Investigations  Contrast enhanced CT scan of abdomen and pelvis  Contrast enhanced MRI of the pelvis  Whole body 18F-Fluoro-deoxy glucose PET-CT
  12. 12.  MRI superior to CT in distinguishing active disease from fibrosis and post-treatment changes  High signal intensity on T2W images: necrosis, inflammation, edema etc.  DWI and DCE images promising in distinction
  13. 13.  Imaging findings of CT and PET in 36 patients (Oct 1997-May 1998)  They had undergone surgery and/or radiation therapy. Tumor recurrence was confirmed by pathologic examination or follow-up studies.  Results:  No significant difference in specificity (p = .2888), but significant differences in sensitivity (p = .0339) and accuracy (p = .0244) sensitivity specificity accuracy PET 100% 94.4% 97.2% CT 77.8% 83.3% 80.5%
  14. 14. Recurrent cervical cancer: Investigations & Initial work up  Baseline documentation with clinical diagram  Pelvic examination (if required under Anaesthesia)  Biopsy of the recurrent local or pelvic disease  Chest X-Ray/CECT chest  Cystoscopy/Sigmoidoscopy  CECT/MRI (DWI)  PET SCAN
  15. 15. Recurrent Cervical Cancer Local recurrence •Central •Lateral pelvic wall •Both •+/- Nodal Distant metastasis •Para-aortic alone •Other sites Local plus distant metastasis
  16. 16. Recurrent cervical cancer After definitive surgery √ No prior radiotherapy After prior radiotherapy With or without surgery
  17. 17. Recurrence after surgery with no prior RT Carcinoma cervix stage 1B1 treated with radical surgery. No adjuvant RT given. Recurrent central disease after 9 months of the completion of therapy. Metastatic work up negative. PS (ECOG 1)  Re-surgery  EBRT and Brachytherapy  EBRT with concurrent CT and brachytherapy  EBRT with concurrent CT and brachytherapy f/b Adjuvant chemotherapy
  18. 18. Recurrence after surgery with no prior RT  Explore surgery for very limited disease  Usually a combination of EBRT and Brachytherapy  Brachytherapy (Interstitial) recommended for patients with >5 mm thickness of recurrence  Concurrent chemotherapy* should be combined in suitable patients *Yu Sun Lee et al. Tumori 96:553-559;2010
  19. 19. Recurrence after prior RT  Surgery  Reirradiation  Systemic therapy
  20. 20. Recurrence after prior RT: Surgical salvage  Patient selection criteria??  Clinical symptoms (Unilateral leg oedema, Sciatic pain, Hydronephrosis)  Size and extent  Disease free interval  Pre-operative counselling??  Type of surgery??
  21. 21. Surgical options Radical hysterectomy Type 2 or 3 (Limited to cervix, <2cm, original stage IB/IIA) Pelvic Exenteration (if central recurrence not amenable to radical hysterectomy and other options already exhausted) Radical surgical resection combined with intra operative radiotherapy (IORT) to exclude normal tissues from the treatment LEER (Inclusion of internal iliac vessels and pelvic muscles) Gadducci A, Tana R, Cosio S, Cionini L. Treatment options in recurrent cervical cancer (Review). Oncol Lett 2010; 1:3.
  22. 22. Pre operative patient evaluation History and Physical examination Studies Disease free interval, stage at diagnosis CT chest, abdomen, pelvis Symptoms of advanced disease Endorectal ultrasonography Peripheral adenopathy Pelvic MRI Severe COPD, limited cardiac reserve PET scanning Nutritional state, emotional stability Hemogram , serum chemistry Pelvic EUA Liver enzymes, serum albumin Review histology, previous radiation therapy and chemotherapy Urine culture, cystoscopy, sigmoidoscopy scopy (rigid) and colonoscopy Enterostomal therapy consultation Pelvic reconstruction team Multidisciplinary oncology evaluation Laparoscopic staging
  23. 23. Counseling • Detailed Discussion with the patient and her family regarding planned procedure, what will be removed, morbidity, altered body image and sexual function. • No guarantee of cure • Stoma Care • Needs for vaginal reconstruction • Formal evaluation by psychologist QOL issues
  24. 24. Outcomes after Exenteration 7-35% of Exenteration performed with a curative intent, are found to have tumor present at the surgical resection margin after thorough pathological evaluation.
  25. 25. 5 year overall survival was 21- 73%
  26. 26. Early (16-71%) 1. Pre operative radiation induced tissue damage 2. Length of operation Late (36-61%)  Fistulae  Obstruction
  27. 27. Recurrence after prior RT: Reirradiation  Patient selection criteria??  Technique of RT??  Radiation dose schedule and fractionation??
  28. 28. Reirradiation: Which patients??  Site of recurrence??  Volume of disease??  Disease free interval??  Histology??  Performance status??
  29. 29. Reirradiation: Which patients??  Central recurrences* (inoperable/unwilling for surgery)/lateral disease  Volume of disease**: <2-4 cm, <100 cc  Disease free interval**  Longer the better  At least > 6-12 month; >2 years  Squamous histology  Good KPS with limited toxicities from prior RT *Mahantshetty U. Brachytherapy 2014 **Zolciak Sivinska. Gynec Oncol 2014
  30. 30. Re-irradiation: What Technique??  Brachytherapy (ICRT/ISBT) +/- EBRT  Interstitial brachytherapy alone  External beam radiotherapy (EBRT)  IORT
  31. 31.  52 patients treated with HDR- ISBT based Reirradiation  Local control rate: 76%  Grade ¾ toxicities: 25%  Tumour size (>4 cm) and DFI (<6 months) important prognostic factors
  32. 32.  N=50  3 year OS and loco-regional control: 56% and 59%  Median RT dose=50 Gray (45-64 Gray)  No Grade 3 or greater acute GI/GU  Grade 3 late toxicity <10%  Poorer OS for DFI <2 years and non-squamous histology (p<0.05)
  33. 33. Patients Rectum-4, Anal canal-6, Cervix-4, Endometrium- 1, UB-1 All patients previously treated with RT Median previous RT dose- 45 Gy 36 Gy/ 6 fractions in 3 weeks Median FU- 11 months LR- 51 %, Median DFS- 8 months One year OS- 46% No grade 3 acute toxicity
  34. 34. Re-irradiation: What Technique??  Minimize volume of irradiation: Conformal  Avoid OARs  Brachytherapy preferred for central, accessible site  EBRT for very lateralized disease/para-aortic  IORT for patients suitable for surgical salvage
  35. 35. Re-irradiation: What Technique??  Brachytherapy (ICRT/ISBT) +/- EBRT  Interstitial brachytherapy alone  External beam radiotherapy (EBRT)  IORT
  36. 36. Radiation: What doses??  Without prior RT  EBRT 45-50 Gray + Brachytherapy (total EQD2 65-75 Gray)  For ReRT  EBRT IMRT/3DCRT: 40-50 Gray (20-25#) SBRT: 20-36 Gray in 3-6 fractions  Brachytherapy alone 20-25 Gray HDR in 4-5 fractions BID  IORT: 10-30 Gray  For palliative RT  20-30 Gray in 5-10 fractions
  37. 37. Clinical outcome after RT  Local control Interstitial Brachytherapy= 25-80% EBRT + Brachytherapy =40-80% IORT + Surgery=20-70% EBRT=50-60%  3-5 year Overall survival: 30-70%
  38. 38. Morbidities and toxicities: RT  Interstitial brachytherapy: Grade 2 toxicities 5-10% Earlier series: Grade 3-4 toxicities15-25%  EBRT: Grade 3 toxicities 5-10%  IORT + Surgery: Grade 2-3 toxicities 25-30% (higher with higher doses)
  39. 39. Systemic therapy in recurrent/persistent/metastatic cervical cancers Single agent versus combination agents??
  40. 40.  Phase III GOG 169 study:  N=264  Pacli/Cis vs cisplatin alone  High RR (36% vs 19%) and PFS (4.8 vs 2.8 months, p<0.001), but no improvement in OS  Phase III GOG 179 study:  N=294  Topo/Cis vs cisplatin alone  High RR (27% vs 13%, p=0.004) , PFS (4.6 vs 2.9 months, p=0.014), and OS (9.4 vs 6.5 months, p=0.017)
  41. 41. Combination versus single-agent therapy  Combination therapy was compared against single- agent cisplatin in a 2012 meta-analysis that included five randomized trials (n = 1114)  Compared with combination platinum-based therapy, single-agent cisplatin resulted in a lower ORR but was associated with less toxicity  Combination of cisplatin plus paclitaxel resulted in OS ranging from 13 to 15 months and PFS from 6 to 8 months compared to OS of 7 - 9 months and PFS of 3 months with cisplatin alone
  42. 42. Systemic therapy in recurrent/persistent/metastatic cervical cancers Single agent versus combination agents?? Preferred combination??
  43. 43. GOG 204  N= 434  Randomized to cisplatin plus paclitaxel [PC] (the reference control arm) or one of three experimental regimens  Cisplatin plus vinorelbine (VC)  Cisplatin plus gemcitabine (GC)  Cisplatin plus topotecan (TC)  VC, GC, and TC are not superior to PC in terms of OS  The trend in RR, PFS, and OS favors PC
  44. 44. Systemic therapy in recurrent/persistent/metastatic cervical cancers Single agent versus combination agents?? Preferred combination?? Cisplatin or Carboplatin??
  45. 45. Cisplatin vs Carboplatin (JCOG0505) • non-inferiority of TC vs TP • n = 250 • Primary end point - OS  A post-hoc analysis showed that prior platinum exposure may impact outcomes  Women not previously treated with cisplatin had a lower OS when treated with carboplatin rather than cisplatin  Median, 13 versus 23 months; HR 0.69  There was no statistically significant difference among women who were previously treated with cisplatin [HR 0.69]
  46. 46. Systemic therapy in recurrent/persistent/metastatic cervical cancers Single agent versus combination agents?? Preferred combination?? Cisplatin or Carboplatin?? Bevacizumab??
  47. 47.  GOG 240 trial  N= 450 , 2:2 factorial design  Randomized to chemotherapy (paclitaxel with cisplatin vs topotecan ) with or without Bevacizumab  A significant improvement in ORR, PFS & OS in favor of Bevacizumab compared with chemotherapy alone  48% vs 36%; 8 vs 6 months (HR 0.67) and 17 vs 13.3 months (HR 0.71), respectively N Engl J Med 2014; 370:734.
  48. 48. Systemic therapy in recurrent/persistent/metastatic cervical cancers  Single agent versus combination agents  Preferred combination: Paclitaxel + Platinum  Cisplatin or Carboplatin: Either of these  Bevacizumab: Preferred in combination with CT
  49. 49. Isolated Para aortic recurrence
  50. 50. Take home message!!  Need to distinguish persistent/recurrent cervical cancer  Comprehensive evaluation of patient prior to treatment  Novel imaging modalities like DWI or PET-CT may be helpful  Management depends on multiple factor and multidisciplinary approach should be preferred  Patient selection for appropriate therapy remains the key  Outcome remains dismal and patient counselling regarding expected outcome and morbidities should be always done

Editor's Notes

  • Positive biopsy at 3 months
  • The rate of early postoperative complications (within 30 days of the surgery) varies from 16 to 71%. One of the most frequent complications is gastrointestinal fistulas with con- nections to the skin, urinary system or vagina. Other com- mon complications include blood clots and leaking anastomoses. There are two main factors influencing the rate of early complications: preoperative radiation- induced tissue damage and the length of the operation.
    The rate of late postoperative complications (occurring more than 30 days after surgery) ranges from 36 to 61%. Late complications include enterocutaneous and vaginal fistulas, ureteral obstruction, bowel obstruction and pyelo- nephritis. These complications arise secondary to postoper- ative adhesions, tumor recurrence and urinary tract infections precipitated by self-catheterization.36

    The mortality asso- ciated with intra and postoperative complications varies from 0 to 12% depending on the study


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